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NEW ERA FOR HEART FAILURE MANAGEMENT
DR KATHERINE FAN
CONSULTANT CARDIOLOGIST
GRANTHAM HOSPITAL
HONG KONG
HEART FAILURE : STILL UNMET NEEDS IN CURRENT ERA • Over past 4 decades, HF patients have derived
substantial benefit from major advances in our understanding of pathophysiology of HF syndrome
• Evolving treatment paradigms
• new medications with novel mechanisms of actions
• BUT Unmet needs still:
• HF hospital discharges (index of population disease burden and economic impact) remain >1 million between 2000 and 2010
• Prevalence will increase aprox 50% between 2012-2030- >8 million people >18 yrs of age with HF
• Aging population
• Improved survival of AMI
• HF survival increases at rate that exceed our impact to prevent development of HF
Cardiac Failure Review 2017;3(1):7-11
CLINICAL COURSE OF HEART FAILURE AND ITS MANAGEMENT
DURATION OF DISEASE STAGES IN EARLY ERA AND PRESENT/ FUTURE ERA
1. Patients in stage B and C may be stable for many years
2. Prolongation of life with anti HF therapies
3. Sudden death in previous era- occurred early in clinical syndrome , incurred with increasing frequency as HF progressed
4. RHF & cardiorenal syndrome herald progression to stage D HF with referral to palliative care
Circulation 2016;133:2671-2686
Major advances: • Treatment based on large RCTs with subsequent incorporation of data into guidelines • Then incorporated into
systematic quality improvement efforts with landmark success
ESC Heart Failure Treatment Guidelines 2016
SACUBITRIL/ VALSARTAN
Neprilysin inhibitor (Sacubitril) Angiotensin II Receptor Blocker
(Valsartan)
PARADIGM-HF STUDY
NEJM 2014;371:993-1004
Randomized 8442 pts with NYHA class II-IV HFrEF EF<40% Trial stopped early after recruiting 25% pts at medican FU 27 mths
PIONEER-HF STUDY
ANGIOTENSIN-NEPRILYSIN INHIBITION IN ACUTE DECOMPENSATED HEART FAILURE
NEJM 2019;380:539-48
SODIUM-GLUCOSE CO-TRANSPORTER 2 INHIBITORS (SGLT2i)
A SERENDIPITOUS STORY IN HEART FAILURE (1)
EMPA-REG OUTCOME trial • Randomized double-
blind placebo controlled trial
• 7020 pts with type 2 DM at high CV risk/ established ASCVD
35% RRR
NEJM 2015;373:2117-2128
FURTHER STUDIES CONFIRMING BENEFITS OF HHF OR CV DEATH
CANVAS Program
NEJM 2017;377:644-657
DECLARE-TIMI 58 Study
NEJM 2019:380:347-357 Non-inferiority
Canagliflozin Dapagliflozin
DAPAGLIFLOZIN IN PATIENTS WITH HEART FAILURE AND REDUCED EJECTION FRACTION
NJEM 2019;381:1995-2008
• Phase 3, placebo-controlled trial
• 4744 pts- NYHA class II-IV
• Dapagliflozin vs placebo in addition to recommended therapy
• With or without DM
26% reduction
18% reduction
30% reduction
17% reduction
Soluble Guanylate Cyclase (sGC) STIMULATOR
THE VICTORIA TRIAL STUDY RATIONALE AND BACKGROUND
Worsening HF is common despite GDMT
There is substantial risk of death or hospitalization after
a worsening HF event
Vericiguat, a novel sGC stimulator, is a potential new
therapy
The Victoria trial assessed the efficacy and safety of vericiguat in patients with HFrEF after
a recent worsening event
(randomized, placebi-controlled, parallel group, multi-center double-blind Phase 3 study)
VIC
TOR
IA Primary endpoint of CV
death or HF hospitalization
-10% RRR
-4.2% ARR
Driven by reduction in HF hospitalization
Reduction in CV death did not reach statistical
significance
“Another win in HFrEF treatment” New physiologic target New target population- worsening HF
VERICIGUAT SUCCESS IN HFrEF MAY NOT APPLY TO SICKEST AFTERALL: VICTORIA POST-HOC ANALYSIS
• Modest but significant clinical advantage in the 86% who had baseline NTproBNP levels 8000 pg/ml or lower
• Further amplified in pts with NTproBNP <4000 pg/ml
• Risk reduction in lowest NTproBNP reached 23%
• [ DAPA HF 26% reduction; PARADIGM-HF 20% reduction]
• “demonstrated the potential upper limit of medication benefit in HFrEF population- subgroup identified the most advanced stage of disease and probably need for non-pharmacological treatment or palliative care”
Endpoints <4000 pg/ml (n=3100)
>4000 to 8000 pg/ml (n=1033)
>8000 pg/ml (n=672)
Primary endpoint
0.77 (0.68-0.88)
0.85 (0.76-0.95)
1.16 (0.94-1.41)
CV death 0.75 (0.6-0.94) 0.84 (0.71-0.99)
1.32 (1.01-1.71)
HF hospitalization
0.78 (0.67=0.9) 0.84 (0.75-0.95)
1.16 (0.94-1.41)
Presented HFA Discoveries Late Breaking Science Session June 19th 2020
HR (95% CI) for outcomes by baseline NT-proBNP in Victoria
MANAGEMENT OF HFrEF IS BREAKING NEW GROUNDS 7 PARALLEL INDEPENDENT PATHWAYS IN HFrEF
Sympathetic nervous system
Renin-angiotensin
system
Aldosterone antagonism
Neprilysin inhibition
SGLT2 receptor inhibition
sGC-cGMP stimulation
Cardiac myosin
IRON DEFICIENCY IN HEART FAILURE
• Iron deficiency (ID) is common in patients with and without anemia with HFrEF
• Estimated prevalence of over 50% in ambulatory patients
• Risk factors: female sex, advanced HF, higher levels of NTproBNP and C reactive protein
• Associated with worse symptoms, quality of life and clinical outcomes of patients with HF across the whole spectrum of LVEF
• Definition of ID in heart failure differs from other conditions of chronic inflammation:
• Ferritin <100 ug/L or ferritin of 100-299 ug/L with a transferrin saturation <20%
• Tremendous research effort into iron deficiency in HF patients:
• Multiple placebo-controlled randomized clinical trials with IV iron in patients with NYHA class II-III HF with EF<45% who met criteria for iron deficiency, regardless of whether anemia was present
• Improved patient-reported outcomes and functional capacity
POTENTIAL MECHANISM INVOLVED IN PATHOGENESIS & DIAGNOSTIC ALGORITHM OF ANEMIA IN HEART FAILURE
Circulation 2018; 138(1):80-98
TREATMENT OF IRON DEFICIENCY IN HF GUIDELINES INTRAVENOUS IRON IS PREFERRED ROUTE
ESC 2016 Guidelines for diagnosis and treatment of acute and chronic heart failure
2017 ACC/AHA HFSA focused update of 2013 ACCF/AHA guideline for management of heart failure
1. IV iron sucrose (max dose 200mg per setting or 2. Ferric carboxymaltose (max dose 1000 mg /week)
CATHETER ABLATION OF AF IN PATIENTS WITH HEART FAILURE TURAGAM ET AL. ANNALS OF INTERNAL MEDICINE 2019; 170(1): 41-50
Decrease in All cause mortality and
HF hospitalization
Improvement in LVEF and
6 minute walk test
IN 2018, THE WORLD OF FUNCTIONAL MITRAL REGURGITATION CHANGED WITH THE PRESENTATION
OF 2 TRIALS- MITRA-FR VS COAPT
PERCUTANEOUS MITRAL REPAIR
• Transcatheter mitral valve repair may be considered for severely symptomatic patients (NYHA class III to IV) with chronic severe primary MR (stage D) who have favorable anatomy for the repair procedure and a reasonable life expectancy but who have a prohibitive surgical risk because of severe comorbidities and remain severely symptomatic despite optimal GDMT for HF (IIB)
AHA/ACC Valvular Disease Guidelines 2014
MitraClip
• 614 patients in US and Canada • MR 3 or 4+ (EROA > 30, RV vol >45 ml) • LVEF 20%-50% and LVESD <70mm • Symptomatic after optimal HF treatment • HF hospitalization within 12 mths and/or BNP >300pg/ml or NTproBNP >1500pg/ml Randomized 1:1 MitraClip +GDMT vs GDMT alone Stricter exclusion criteria
Hospitalization for Heart Failure All cause mortality
N Engl J Med 2018;379:2307- 2318 * Additionally, all 10 secondary endpoints met statistical significance In favor of MitraClip with GDMT over GDMT alone.
• 304 patients in France • Inclusion:
• EF 15-40% • No LVESD criteria • RV vol >30ml or EROA >20mm2 (actual mean EROA was 31) • Minimum of 1 hospitalization for HF within 12 mths
preceding rndomization • Primary outcome: all cause mortality + HF hospitalization at 12
months
WHY ARE THE COAPT RESULTS SO DIFFERENT FROM MITRA-FR? POSSIBLE REASONS
MITRA-FR (n=304) COAPT (n=614)
Severe MR entry criteria Severe FMR by EU guidelines: EROA >20mm2 or
RV >30ml/beat
Severe FMR by US guidelines: EROA >30mm2 or RV >45ml/beat
EROA 31±10 𝑚𝑚2 41±15𝑚𝑚2
LVEDV 135 ±35 𝑚𝑙/𝑚2 101 ±34 𝑚𝑙/𝑚2
GDMT at baseline and FU Receiving HF meds at baseline- Allowed variable adjustment in each group during FU per “real
world” practice
CEC confirmed pts were failing maximally tolerated GDMT at baseline- few major changes
during follow-up
Acute results : No clip/ >3+ MR 9%/ 9% 5%/ 5%
Procedural complications 14.6% 8.5%
12 month MitraClip >3+ MR 17% 5%
FUNCTIONAL MR BEFORE AND AFTER COAPT
Before After
MR is a risk marker MR is a risk factor
MR= Color jet area MR= EROA
Hugh LV volume is bad Hugh LV volume is really bad
ACC/AHA IIB indication for surgery
ACC/AHA IIA indication for MitraClip?
Interventional Cardiologist
Cardiac surgeon Imaging
Cardiologist
Advanced HF cardiologist
Interventional cardiologist
Heart surgeon
Imaging Cardiologist
Advanced Heart Failure Cardiologist
The ‘New’ Heart Team?
Patient selection, medical treatment and procedural timing is key for success
• Novel paradigm/ theory provides a strong pathophysiological basis for selecting patients for specialized interventions and explains the apparently discordant findings from randomized trials
• Concept:
• Characterization of MR as proportionate or disproportionate to LVEDV appears to be critical to the selection of an optimal treatment for patients with CHF and systolic dysfunction
• A patient with EROA/LVEDV ratio well below the line of proportionality has non severe MR and would not be expected to benefit from any intervention directed at mitral valve
Grayburn P et al. JACC Img 2018
LEFT VENTRICULAR ASSIST DEVICE (LVAD)
DOMAIN MANAGEMENT APPROACH TO HEART FAILURE
HF INTERVENTION DURING EARLY PHYSIOLOGIC CHANGE: PROACTIVE VS REACTIVE
Hospital
HF MANAGEMENT IN NEW ERA INTERNET OF THINGS (IoT)
• Models for the outpatient management of acutely decompensated heart failure have shown that ambulatory infusion of decompensated HF can reduce all-cause hospitalization at 30 days 1
• Successful outpatient management of HF (Proactive):
• Investment in home-based healthcare services
• 24 hours telephone access for advice
• Protocol for the management of electrolytes and changes in renal function
• One tools with immense potential to continue care – TELEMEDICINE
• Improve communication with patients
• Triage need for inpatient care or acute visits
• Monitor patients while they are in their communities 1. JACC Heart Failure 2016;4:1-8
CARDIAC CARE CONNECTED TECHNOLOGY PLATFORM
Danger zone
Action Range
Ideal Range
Alert Threshold
Telemonitoring for Heart Failure: Decision Support
• For patients for health maintenance (majority)
• Daily to maintain health envelope • Diet • Medications (principally diuretics)
• For Health Professionals for Alerts • “Traffic Lights” of risk status • Identify, prevent and manage crisis • Schedule tests • Alter care plan targets
ARTIFICIAL INTELLIGENCE: THE FUTURE OF CARDIOLOGY
• “the theory and development of computer systems able to perform tasks normally requiring human intelligence”
• For example: automated predictions of cardiovascular disease risk score and HF diagnosis
• Automated method to interpret ECHO
Circulation 2018;138:1623-1635
Circulation 2016;133:2671-2686
CONCLUSIONS
• Residual risk remains in heart failure due to inadequate GDMT implementation
• Targeting alternate parallel pathways may be associated with improved outcomes and modulation (eg SGLT2 inhibition, sGC-cGMP, cardiac myosin activation)
• Non pharmacological treatments play increasing important roles
• Physician and patient education, GDMT implementation and targeting all pathways and remote monitoring are important heart failure care.
5 IMAGINATIVE PREDICTIONS FOR TREATMENT OF HEART FAILURE IN 2028 BY DR MILTON PACKER
EUROPEAN HEART JOURNAL 2018;39 (1): 5-7
• 1. Heart failure with a preserved ejection fraction will be broken into distinct phenotypes. The most common phenotype – that associated with obesity- will be treated as a neurohormonal disorder
• 2. The next wave of new pharmacological agents for heart failure with a reduced ejection fraction will focus on drugs that induce the cellular housekeeping process of autophagy
• 3. Unless major changes take place in the pricing or uptake of new pharmaceuticals, drug development for heat failure will cease. The risks and expense of new drug development for these patients will exceed the likelihood of a meaningful return on investment.
• 4.Most patients with chronic heart failure will be managed by specialist practitioners who will not be cardiologists and may not be physicians
• 5. Cell- and gene-based treatments will fail, but because of advances in mechanical devices that provide effective circulatory support, no one with adequate financial resources will die of heart failure involuntarily
THANK YOU!
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